A drug that could target the cause of Huntington's disease has been safely and effectively tested in mice and monkeys, and human trials will follow. The progress is due to be presented at the 68th Annual Meeting of the American Academy of Neurology.
Huntington's disease (HD) is a rare, hereditary condition that causes uncontrolled movements, cognitive and emotional difficulties and, eventually, death.
HD passes from parent to child through a mutation in the huntingtin gene (HTT mRNA). This mutation leads to the production of a huntingtin (Htt) protein, and this causes the disease.
A child whose parent has the mutated gene will have a 50% chance of inheriting the mutation. Everyone who has it will eventually develop the disease.
While tetrabenazine was approved by the Food and Drug Administration (FDA) in 2008 to treat Huntington's chorea, the involuntary writhing movements that are symptomatic of the disease, there is so far no way of curing or preventing HD.
Antisense drug IONIS-HTTRx delays onset and reverses symptoms
IONIS-HTTRx is an antisense drug that inhibits the production of the huntingtin protein by "silencing" the gene.
Studies so far have indicated that antisense drugs can help to delay progression of the disease and can reverse the disease phenotype.
In one mouse model, motor deficits improved within a month of beginning the treatment, and, 2 months after treatment termination, they were restored to normal.
Another mouse study indicated an improvement 8 weeks after starting treatment, and this continued for at least 9 months after stopping the treatment.
In monkeys, an antisense drug caused reductions in the huntingtin gene and protein throughout the central nervous system, at levels that depended on the dose.
A 50% reduction of cortical huntingtin levels was observed in monkeys, correlating with 15-20% reduction in the caudate nucleus of the brain. The caudate nucleus is located in the basal ganglia, which plays a key role in sensorimotor coordination.
Further tests in mice and monkeys suggest that IONIS-HTTRx is well tolerated, with no dose-limiting side effects.
Next step: phase 1/2a clinical study
The next step is to trial the drug in humans. A phase 1/2a clinical study is now under way.
The drug is administered in four doses at monthly intervals. As antisense drugs do not cross the blood-brain barrier, IONIS-HTTRx is injected into the cerebral spinal fluid via an intrathecal injection in the lumbar space.
The researchers will evaluate the safety and tolerability of the drug at different doses. They will also characterize the drug pharmacokinetics and examine the effects of the therapy on specific biomarkers and clinical outcomes.
Clinical study principal investigator Dr. Blair R. Leavitt, of the University of British Columbia in Vancouver, Canada, says:
"It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease. Right now we only have treatments that work on the symptoms of the disease."
However, Dr. Leavitt notes that it will still be several years before the drug will be ready for use in human clinical practice.
Medical News Today reported last year that a new understanding of the effect of HD on DNA could lead to future breakthroughs in the search for a cure.